The current obesity epidemic in the US is the major contributor to the soaring rates of metabolic diseases and to skyrocketing health care costs. Yet the molecular and pathological mechanisms by which obesity induces metabolic disorders remain incompletely understood, and therapeutic interventions for obesity and related metabolic abnormalities are limited. In recent years, thousands of long non-coding RNAs lncRNAs have been identified and constitutes a significant portion of mammalian genomes. Interestingly, half of SNPs associated with diseases including metabolic disease fall in the noncoding regions suggesting that dysfunction of lncRNAs might be pathogenic. However, the pathophysiological roles of most lncRNAs remain poorly understood and their implications in metabolic disorder are largely unexplored. To systemically identify lncRNAs that might be involved in metabolic regulation, we performed genome-wide screens to compare lncRNA profiles in mice under different metabolic states or between lean and obese mice. These screens identified hundreds of lncRNAs whose expressions were strongly regulated by metabolic conditions or essential nutrients. Interestingly nutrient-regulated lncRNAs often exhibit altered expression in obese and diabetic mice. To further investigate the physiological role of lncRNAs, we have generated mice with tissue-specific loss-of-function of selected lncRNAs. We are carrying out extensive analyses to determine the impact of depletion of lncRNAs in key metabolic tissues on systemic lipid and glucose metabolism. In addition, we are also pursuing the pathological role of lncRNAs in obese and diabetic mice and corroborate our findings using patient samples.